1alpha-methyl-delta2-androstenes



Patented June 6, 1967 United States Patent cc 3,324,152

The method of the present invention proceeds in ac- 3,324,152 cordance with the following reaction mechanism:

1a-METHYL-A -ANDROSTENES- Hans Miiller and Rudolf Wiechert, Berlin, Germany, as- 0R signors to Schering AG, Berlin, Germany 6 No Drawing. Filed Feb. 12, 1964, Ser. No. 344,191 Claims priority, application Germany, Apr. 18, 1963, CH3

Sch 33,126 16 Claims. (Cl. 260-397.5)

The present invention relates to la-methyl-A -andro- 10 stenes, and more particularly to la-met hyl-A androstene- O: I 17 8-01 compounds and derivatives thereof, and to the H method of production of such compounds.

It is a primary object of the present invention to provide a new series of compounds, namely 1a-methyl-A -5aandrostene-17 3-ol compounds.

It is another object of the present invention to provide H a method of producing such compounds.

It is yet another object of the present invention to pro- I (a) msylatmg vide a new series of compounds which have a highly 20 H0 W A 20; effective anabolic .action, and which can be administered 11 orally to achieve such action.

It is still a further object of the present invention to OR provide such compounds which while having a strong I anabolic action have substantially no androgenic side effect. 1H3

Other objects and advantages of the present invention will be apparent from a further reading of the specifica- L/ tion and of the appended claims.

With the above and other objects in view, the present invention mainly comprises a compound of the formula: H

wherein R is selected from the group consisting of hy- O drogen and acyl, acyl being preferably derived from a 11 lower aliphatic carboxylic acid, and wherein R is selected from the group consisting of hydrogen and lower alkyl,

wherein the alkyl can be either saturated or unsaturated.

In accordance with the method of the present invention,

1a-methyI-Sa-andrOstane-I7/8-ol-3-one-17-ester is, in per I se known manner, preferably using sodium borohydride,

first reduced to a mixture of the two corresponding epii mers of la-methyI-Su-androstane-3,17,8-diol-17-ester. This H VII mixture is then, also in per se known manner, tosylated,

and the crude tosylated reaction product filtered over neu- OH eson tral aluminum oxide, whereby a 17-ester of lea-methyl- A -5a-androstene-l7B-o1 is obtained. This compound is 1H1 then, depending on the desired value for R in the final VII product, saponified to the free Iu-rnet'hyl-A -Sa-androstene-17fl-ol, whereupon the latter can, if desired, by the I use of the desired acid of the formula R OH or a reactable acid derivative, again esterified. H

It is desired that R in the final product be an alkyl, the

free 1a-methyl-A -5u-androstene-175-01 is, in per se known manner, preferably by means of chromic acid, oxidized to A] la-methyl-A -5a-androstene-17-one, and this compound is then, also in per se known manner, either by means of CH3 I Grignardation converted to a 17a-position alkyl group, or

an analogously introduced 17u-ethinyl group is subsequently reduced to a vinyl or ethyl group. The 17/3-position hydroxyl group can then be subsequently esterified with the desired acyl.

- VIII VII In the above formulas R is acyl, R is hydrogen or acyl, and R is a lower saturated or unsaturated alkyl.

The new compounds of the present invention can be administered orally to give a strong anabolic action, and even at very high doses the androgenic side efiect is practically negligible.

Thus, for example, the l11,17m-dimethyl-A -5u-androstene-l7fi-ol in the levator-ani test on castrated rats is anabolically three times as active as the 17a-methyltestosterone with which it is compared. Even at higher doses, the androgenic side efiect is only about /6 that of the 17a-methyl-testosterone.

The great separation and action between the anabolic and androgenic activity is extremely advantageous.

la-methyI-A -Sa-androstene-l7fl-ol is also in suitable doses upon per oral administration anabolically equally as strong as 17u-methyl-testosterone and at the same time however exhibits no androgenic side effect. 1a-methyl-A 5a-androstene-17 3-ol also proves to be practically equal with respect to anabolic and androgenic activity upon per oral administration as 1-methyl-A -androstene-l7p-ol-3- one.

The compound 1a-methyl-l7a-ethinyl-A -5a-andro tene- 1713-01 exhibits in'particular the ability to inhibit the gonadotropin-elimination, since after its administration an elimination action on the growth of the testes and prostate can be noticed. In addition, ovulation inhibition after subcutaneous administration is observed.

In comparison to the new lot-methyl compounds of the present invention, the corresponding lwdesmethyl compounds (compare Chem. and Ind. 1961, page 1962 and US. Patent No. 2,996,524) besides exhibiting a strong anabolic action at the same time exhibit an un desired strong androgenic side effect.

The following examples are given to further illustrate the present invention. The scope of the invention is not, however, meant to be limited to the specific details of the examples.

Example 1 1.97 g. of NaBH are introduced in small portions at room temperature under stirring to a solution of 15 g. of 1a-methyl-androstane-175-01-3-one-17-acetate (produced according to German Patent No. 1,122,944, German Auslegeschrift No. 1,131,667) in 650 cc. of methanol and 31.6 cc. of water. After the introduction is completed, the reaction mixture is stirred for an additional 20 minutes, and the reaction mixture is then poured into ice cold sodium chloride solution. The resulting precipitate is filtered off, washed until neutral, and while still wet taken up in methylene chloride. The methylene chloride phase is dried and evaporated. There remains a crystallisate which melts at 138 C. and a mixture of 30cand 3/3-hydroxy compound. The yield is practcially quantita- 4.- tive. Upon thin layer chromatogram it is shown that the starting compound, the 3-ketone, is no longer present.

15 g. of the epimer mixture, 15 g. of p-toluene sulfochloride and 22.5 cc. of absolute pyridine are allowed to stand overnight at room temperature. The reaction mixture is then stirred into 1 liter of sodium bicarbonate solution. The precipitate is filtered olf, dissolved in methylene chloride, washed to neutral, dried and evaporated.

There remains 1a-methyI-Sa-androstane-3e,17/9-diol-3- tosylate-17-acetate as a crystallizable oil in practically quantitative yield.

The crude product (approximately 18 g.) is dissolved in benzene and introdued into a column with 1 kg. of aluminum oxide (neutral, 1% water content). By eluation with benzene with increasing amounts of ethyl acetate, 9.1 g. of la-methyl-A -Sa-androstene-17,8-ol-17-acetate is obtained as an oil, which recrystallizes from pentane, melting at 52-53 C.

Example 2 9.1 g. of the 1a-methyl-A -Sa-androstene-l7fl-ol-l7-acetate produced according to Example 1, in 106 cc. of methanol are heated under nitrogen and refluxing with 10.5 g. of potassium carbonate in 27 cc. of water. The heating is for minutes. 10.5 cc. of glacial acetic acid are then added. The reaction mixture is cooled and diluted with water. The precipitate is filtered off under suction, Washed until neutral and dissolved in methylene chloride. The methylene chloride phase is dried over sodium sulfate and evaporated. The residue consists of la-methyI-A -Saandrostene-17fl-ol, which recrystallizes from isopropyl ether and melts at 124-125 C. The yield amounts to 6.45 g.

Example 3 2.5 g. of the 1cvmethyl-A -5a-androstene-l7fi-ol produced according to Example 2 are heated for 1.5 hours at 125 C. with 10 cc. of absolute pyridine and 5 cc. of enanthic acid anhydride. 0.2 cc. of water are then added and the reaction mixture is then heated for 1 hour at C. Pyridine and excess enanthic acid anhydride are subsequently distilled off with steam. The reaction product is extracted with methylene chloride. The methylene chloride phase is dried over sodium sulfate and evaporated.

There is thus obtained 2.33 g. of Ia-methyI-A -Sa-androstene-17fi-ol-17-enanthate as an oil.

Example 4 2.5 g. of the 1a-methyl-A -5a-androstene-175-01 produced according to Example 2 are dissolved in 65 cc. of acetone, the solution is cooled to 15 C., and 660 mg. of chromium-(VI)-oxide in 2.2 cc. of 8 N sulfuric acid are added dropwise under stirring to the cooled solution. The stirring is continued for an additional 2 minutes and the reaction solution is then poured into ice water, xtracted with methylene chloride, the methylene chloride phase is washed successively with sodium thiosulfate solution, then sodium bicarbonate solution, then water, dried over sodium sulfate and then evaporated. What remains is an oil (1a-methyl-A -Sa-andrcstene-l7-one) which serves as a crude product for Grignardation. The yield amounts to 2.5 g.

2.4 g. of crude 1a-methyl-A -Su-androstene-17-one in cc. of absolute benzene are added dropwise to cooled Grignard solution, produced from 3.52 g. of magnesium turnings in 39 cc. of absolute ether and 9.04 cc. of methyl iodide in 25 cc. of absolute ether, and the reaction mixture stirred for 4 hours at room temperature under nitrogen. Thereupon concentrated aqueous ammonium chloride solution is very carefully added under cooling from the outside with ice. The reaction mixture is acidified with dilute hydrochloric acid and extracted with ether. The ethereal phase is washed neutral, dried and evaporated. The residue is subjected to chromatography over silica Example 5 Cooled Grignard reagent prepared from 468 mg. of magnesium turnings in 4.8 cc. of absolute tetrahydrofurane and 1.45 cc. of ethyl bromide in 4.8 cc. of absolute tetrahydrofurane are added to 7 cc. of absolute tetrahydrofurane through which acetylene had previously been conducted for 20 minutes. This results in an increase in the temperature to 45 C. Acetylene is then again conducted therethrough until the temperature again falls.

Thereupon 225 mg. of the crude Ia-methyI-A -Saandrostene-17-one, produced according to Example 4, in 4.8 cc. of absolute tetrahydrofurane are added dropwise to the reaction mixture. During the dropwise addition acetylene is always still conducted through the reaction mixture. The reaction mixture is then heated under nitrogen and stirring for 21 hours at 70 C. on a hot oil 'bath. After cooling to 5 C., concentrated aqueous ammonium chloride solution are slowly added until no reaction occurs. It is then extracted with ether, the organic phase washed with water until neutral, dried over sodium sulfate, concentrated to dryness under vacuum and the residue is subjected to chromatography over silica gel water content).

After eluation with equal parts of carbon tetrachloride and methylene chloride, and recrystallization from pentane there is obtained 100 mg. of 1lit-methyl-I7OL-EthlHYI-A -SOL- androstene-17 3-ol having a melting point of 9293 C.

Without further analysis, the foregoing will so fully reveal the gist of the present invention that others can by applying current knowledge readily adapt it for various applications without omitting features that, from the stand- What is claimed as new and desired to be secured by Letters Patent is:

in the acyl is derived from a hydrocarbon carboxylic acid.

3. A compound of the formula:

wherein R is lower alkyl.

4. A compound of the formula:

1'1 wherein R is lower alkinyl.

5. A compound of the formula:

wherein R is an acyl derived from a hydrocarbon carboxylic acid; and wherein R is a hydrocarbon radical selected from the group consisting of alkyl and alkinyl radicals of up to 5 carbon atoms.

6. i(methyl-A 6wandrostene-17,3-01-17-acetate.

7. 1a-methyl-A fia-androstene--01-17-enanthate.

8. 1a,17a-dimethyI-A -Sa-andrOstene-17,8-01.

9. la-methyl-l7a-ethinyl-A -5a-androstene-176-01.

10'. la-methyl-l7a-ethyl-A -5a-androstene-17,8-01.

11. The method which comprises reducing lot-methyl- 5a-androstane-17 3-ol-3-one-17-acylate to the corresponding epimers of 1a-methyl-5u-androstane-3,17fl-diol-17- acylate; tosylating said epimers so as to form the corresponding la-methyl-5a-androstane-3,17,8-diol-3-tosylate- 17-acylate; and filtering the thus-obtained crude tosylated reaction product in an organic solvent through neutral aluminum oxide to obtain thus purified Ia-methyI-A -Suandrostene-l7 3-ol-l7-acylate.

12. The method which comprises reducing lot-methyl- 5a-androstane-17 3-ol-3-one-l7-acylate to the corresponding epimers 1a-methyl-5a-androstane-3,17 3-diol-17-acylate; tosylating said epimers so as to form the corresponding la-methyl-5a-androstane-3,17,B-diol-3-tolylate-17-acylate; filtering the thus-obtained crude tosylated reaction product in an organic solvent through neutral aluminum oxide to obtain thus purified 1a-methyl-A -Sa-andmstene- 17,6-ol-17-acylate; and saponifying the thus formed 10cmethyl-A -5a-androstene-176-01-17-acylate so as to form the corresponding 1u-methyl-A -5a-androstene-17,8-01.

13. The method which comprises reducing ila-methyl- Sa-androstane-l7B-ol-3-one-17-acylate to the corresponding epimers 1a-methyl-5u-androstane-3,17,8-diol-17-acylate; tosylatlng said epimers so as to form the correspondin g 1m-methyI-S -andrOstane-B ,17,B-diol-3-tolylate-l7-acylate; filtering the thus-obtained crude tosylated reaction solvent through neutral aluminum oxide to obtain thus purified 1a-methyl-A -5u-androstene- 17fl-ol-17-acylate; saponifying the thus formed lot-methyl- A -5a-androstene-175-01-17-acylate so as to form the corresponding 1a-methyl-A -5a-androstened7fi-ol; oxidizing the same to the corresponding 1a-methyl-A -5a-androstene-17-one; and converting said 1a-methyl-A -5a-androstene-17-one to the corresponding lot-methyl-lh-loweralkyl-A -5a-androstene-173-01 by Grignardation.

14. The method which comprises reducing lot-methyl- Sa-androstane-l7/3-ol-3 one-l -acylate to the corresponding epimers 1a-methyl-5a-androstane-3,17/8-diol-17-acylate; tosylating said epimers so as to form the corresponding 1a-methyl-Sa-androstane-3, 17fi-diol-3-tolylate-17-acylate; filtering the thus-obtained crude tosylated reaction product in an organic solvent through neutral aluminum oxide to obtain thus purified 1a-methyl-A -5u-androstene- 17,6-ol-17-acy1ate; saponifying the thus formed lot-methyl- A -Sa-andmstene-17,8-ol-17-acylate so as to form the corresponding la-methyl-A -5a-androstene-17-ol; oxidizing the same to the corresponding 1a-methyl-A -5a-androstene-l7-one; converting said 1a-methyl-A -5u-androstene- 17-one to the corresponding lot-methyl-l7a-loweralkinyl- A -5a-androstened7B-ol by Grignardation; and reducing said 1 a-methyl-17m-loweralkinyl-A -5a-androstene-17 9-01 to the corresponding 1a-methyl-17a-loweralkenyl-A -5aandrostene-17fl-ol.

15. The method which comprises reducing 1OL-I1'16thy1- 5a-androstane-17/8-ol-3-one-17-acylate to the corresponding epimers 1a-methyl-Sot-androstane-3-17B-dio1-17-acylate; tosylating said epimers so as to form the corresponding la-methyI-Sm-andrOStane-S,17B-diol-3-tolylate-17-acylate; filtering the thus-obtained crude tosylated reaction product in an organic solvent through neutral aluminum oxide to obtain thus purified 1a-methy1-A -Son-androstene- 17/3-ol-17-acylate; saponifying the thus formed lot-methyl- A -Su-androstene-17 3-ol-17-acy1ate so as to form the corresponding 1a-methyl-A -Sa-androstene-17-01; oxidizing the same to the corresponding Iu-methyI-A -Sa-andmstene-17-one; and converting said Im-methyI-A -Su-andmstene-l7-one to the corresponding lu-methyl-lh-loweraIkinyI-A -Su-androstene-175-01 by Grignardation.

16. The method which comprises reducing lot-methyl- 5a-androstane-17B-o1-3-one-17-acylate to the corresponding epimers 1a-methyl-Sa-androstane-3,17B-dio1-17-acylate; tosylating said epimers so as to form the corresponding 1a-methyI-Stx-andmstane-3,17B-diol-3-tosylate-17-acylate; filtering the thus-obtained crude tosylated reaction 8 product in an organic solvent through neutral aluminum oxide to obtain thus purified 1u-methyl-A -5u-androstene 17fi-ol-17-acy1ate; saponifying the thus formed lot-methyl- A -5a-androstene-17fl-o1-17-acylate so as to form the corresponding 1a-methyI-A -Sa-androstene-17,8-01; oxidizing the same to the corresponding 1a-methyl-A -5a-androstene-l7-one; subjecting said 1a-methyI-A -Su-androstene- 17-one to Grignardation so as to form the corresponding l7fl-hydroxyl-l7ot-lower hydrocarbon derivative; and esterifying the same so as to form the corresponding 17;?- acylate.

References Cited UNITED STATES PATENTS 2,996,524 8/1961 Huffman 260-397.5 3,009,934 11/1961 Counsell et a1. 2603974 3,018,298 1/1962 Klimstra et a1. 260-397.4 3,167,547 1/1965 Cross 260-23955 LEWIS GOTTS, Primmy Examiner.

ELBERT L. ROBERTS, Examiner. 

3. A COMPOUND OF THE FORMULA: 